Substituted mercapto benzimidazoles

ABSTRACT

Compounds of the following formula   WHEREIN Z is ethylene or propylene; R1 is hydrogen, methyl, ethyl, phenyl, nitrophenyl, benzyl, phenethyl, tolyl or xylyl; R2 is alkyl of from 1 to 5 carbons, benzyl, nitrobenzyl, phenethyl, nitrophenethyl, alkoxycarbonylalkylene wherein the alkoxy radical has from 1 to 5 carbons and the alkylene radical has 1 to 3 carbons, dialkylaminoalkylene wherein the dialkyl radicals have from 1 to 3 carbons and the alkylene radical has 2 or 3 carbons, alkanoyl of from 2 to 18 carbons, benzoyl, a substituted benzoyl wherein said substituent is halogen, alkyl of 1 to 3 carbons or phenyl, phenylmethylcarbonyl, phenethylcarbonyl,   wherein Z and R1 are as defined above,   WHEREIN ALKYL IS OF 1 TO 5 CARBONS, OR   R4 is alkyl of 1 to 3 carbons, phenyl, benzyl or phenethyl; X is O or S; R3 is hydrogen, halogen, nitro, amino, cyano, trifluoromethyl, alkyl of from 1 to 3 carbons, alkoxy of from 1 to 3 carbons, dialkylamino wherein each alkyl radical is from 1 to 3 carbons, alkanoyl of from 2 to 6 carbons, or benzoyl; and n is 1 or 2; are disclosed. These compounds exhibit antiinflammatory activity.

United States Patent [1 1 Rovnyak et a].

[ Dec. 16, 1975 SUBSTITUTED MERCAPTO BENZIMIDAZOLES [75] Inventors:George Rovnyak, Hopewell;

Venkatachala L. Narayanan, Hightstown; Rudiger D. Haugwitz, Titusville;Christopher M. Cimarusti, Hamilton, all of NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: July 29, 1974 21 Appl. No.: 492,644

[52] US. Cl. 260/306.7 T; 260/243 R; 424/246;

424/270 [51] Int. Cl. C07D 235/28 [58] Field of Search 260/3067 T, 243 R[56] References Cited UNITED STATES PATENTS 8/1973 Narayanan et al.260/306.7 T

OTHER PUBLICATIONS Bost et al., J. Am. Chem. 800., 65 (1943), pp.900-901.

Wagner et al., Synthetic Organic Chemistry, N.Y., Wiley, 1953, pp. 645and 787-788.

Primary ExaminerR. Gallagher Attorney, Agent, or Firm-Lawrence S.Levinson; Merle J. Smith; Stephen B. Davis [57] ABSTRACT Compounds ofthe following formula (Rb E: K R

' wherein Z is ethylene or propylene; R is hydrogen,

wherein Z and R are as defined above,

wherein alkyl is of 1 to 5 carbons, or

R is alkyl of l to 3 carbons, phenyl, benzyl or phenethyl; X is O or S;R is hydrogen, halogen, nitro, amino, cyano, trifluoromethyl, alkyl offrom 1 to 3 carbons, alkoxy of from 1 to 3 carbons, dialkylamino whereineach alkyl radical is from 1 to 3 carbons, alkanoyl of from 2 to 6carbons, or benzoyl; and n is l or 2; are disclosed. These compoundsexhibit antiinflammatory activity.

8 Claims, No Drawings 1 SUBSTITUTED MERCAP'IQBENZIMIDAZOLES BACKGROUNDOF THE INVENTION The prior art discloses the use of substitutedbenzimidazolinone compounds as antiinflammatory agents as note U.S. Pat.No. 3,813,409 issued on May 28, 1974. It has been discovered thatsubstituted mercapto benzamidazole compounds are also useful asantiinfiammatory agents.

This invention relates to new compounds of the formula:

R3 n C) S R pr if dialkylaminoalkylene wherein each alkyl radical has 1to 3 carbons and the alkylene radical has 2 or 3 carbons; alkanoyl offrom 2 to 18 carbons; benzoyl;

substituted benzoyl wherein said substituent is halogen, alkyl of l to 3carbons, or phenyl; phenylmethylcarbonyl; phenethylcarbonyl;

wherein Z and R are asdefincdabove;

wherein alkyl-is of l'to' 5 carbons; or

ent, for example, where R is dialkylaminoalkylene or R is amino ordialkylamino form physiologically acceptable acid addition salts withinorganic and organic acids. These acid-addition salts frequentlyprovide useful means for isolating the products from reaction mixturesby forming the salt in a medium in which it is insoluble. The free basemay then be obtained by neutralization,'e.g.', with a base sulchassodium hydroxide. Then any other salt may again by formed from the freebase and the appropriate inorganic acid. lllustrative are thehydrohalides, especially the hydrochloride and hydrobromide which arepreferred, sulfate, nitrate, phosphate, tartrate, maleate. fumarate,citrate, succinate, methanesulfonate, benzenesulfonate,toluenesulfonate, and the like.

substituted benzoyl, phenylmethylcarbonyl, phenethylcarbonyl,alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, or 2-phenylethoxycarbonyl are prepared by treating the substitutedbenzimidazole-Z-thiol of formula II with a compound of formula III at amolar ratio of from about 1:1 to about 1:3 at a temperature of fromabout 25C to about C for about 0.5 to about 24 hburs in the presence ofa polar aprotic solvent such as dimethylformamide (DMF) ordimethylsulfoxide (DMSO) or an ethereal solvent such as tetrahydrofuran(THF) and a strong base such as sodium hydride, sodium amide, sodium orpotassium alkoxy salts, or sodium or potassium in the presence of liquidammonia.

The substituted benzimidazole-Z-thiols of formula ll are prepared fromthe appropriate 2-(o-aminoanilino)- 2-thiazoline of formula W by heatingwith carbon disulfide in alcohol, or by the action of thiophosgene inchloroform, or by heating with potassium ethyl Xanthate (Van Allan etal., Organic Syntheses, Collective Vol. 4, p. 569-570).

The substituted benzimidazole-Z-thiols of formula II may exist in atautomeric form wherein a hydrogen atom is attached to the nitrogen atomand the double bond is exocylic.

The 2-(o-aminoanilino)-2-thiazolines of formula IV are prepared byreacting o-phenylenediamine of formula V with an haloalkylisothiocyanateof formula VI as taught in US. Pat. No. 3,816,444 issued on June 1 1,1974 to Narayanan et a].

(V) (VI) 3 H2 haloZl-NCS NH2 (R (VIII) Compounds of formula I where R isare prepared by, reacting the substituted benzimidazole-Z-thiol offormula II with a haloalkylisothihan ocyanate of formula VI at a molarratio of from about 1:1 to about 1:3 at a temperature of from about 25Cto about C for from about 0.5 to about 24 hours in the presence of apolar aprotic or ethereal solvent and strong base as described above.Similarly, compounds of formula I where R is are prepared by reactingthe substituted benzimidazole-Z-thiol of formula II with an isocyanateor isothiocyanate of formula alkyl- N=C=X II) at a molar ratio of fromabout 1:1 to about 1:3 at a temperature of from about 25C to about 150Cfor about from 0.5 to about 24 hours in the presence of a non-polaraprotic solvent such as benzene, toluene, xylene, 1,2-dimethoxyethane(glyme), or bis(2- methoxyethyl)ether (diglyme) or any of the polaraprotic solvents and strong bases as described above.

The compounds of formula VIII are prepared by reacting themercaptobenzimidazole of formula 5 -H (R W with R -halo in the presenceof a polar aprotic or ethereal solvent and strong base. Themercaptobenzimidazole of formula [X is prepared from anophenylenediamine of formula V by heating with carbon disulfide inalcohol, by the action of thiophosgene in chloroform, or by heating withpotassium ethyl Xanthate (Van Allan et al., supra).

The preferred compounds are those wherein R is hydrogen; n is 1; R ishydrogen, halogen, nitro, or alkyl of 1 to 3 carbons; and R is benzoylor substituted benzoyl.

The most preferred compounds are those wherein Z is ethylene; R ishydrogen, methyl or Cl, especially hydrogen; and R is (p-phenyl)benzoyl.

The compounds of this invention are useful as antiinflammato ry agentsand are effective in the prevention and inhibition of granuloma tissueformation in warm blooded animals, and may be used, for example, in amanner similar to phenylbutazone or indomethacin. They may be used todecrease joint swelling, tenderness, pain and stiffness in mammalianspecies, e.g., in conditions such as rheumatoid arthritis. The compoundsof this invention or a physiologically acceptable acid-addition saltthereof as described above may be compounded according to acceptedpharmaceutical practice for administration orally or by injection.Suitable oral dosage forms are tablets, capsules, elixirs, or powders,while solutions or suspensions are suitable for injection. The quantityadministered may be from about 25 mg. to about 2 gm. per day, andpreferably from about 50 mg. to about 200 mg. per day.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale.

EXAMPLE 1 1 ,1 -Biphenyl ]-4-carbothioic acid, S-[1-(4,5-dihydro-2-thiazolyl l lj-benzimidazol-Z- yl ester a.2-(o-Aminoanilino)-2-thiazoline A solution of 7.8 g. (0.07 mole) ofo-phenylenediamine and 1 1.9 g. (0.07mole) of 2-bromoethylisothiocyanate in 150 ml. of dry glyme is stirred at room temperaturefor one hour. The solution is decanted and the remaining viscous oil istaken up in water, basified with K CO and extracted with warm CHCl Thecombined CHCl extracts are washed with water and cooled in an ice-bath.The precipitated crystals are collected by filtration and dried yielding6.6 g. of 2-(0- aminoanilino)-2-thiazoline, Recrystallization from CHClyields an analytical sample, m.p. 165167.

b. 1-( 4,5-Dihydro-2-thiazolyl 1 lj-benzimidazole-Z- thiol A solution of7.0 g. (0.04 mole) of 2-(oaminoanilino)-2-thiazoline from part (a), l1.2 g. (0.15 mole) of carbon disulfide and 2.8 g. (0.05 mole) of KOl-Iin ml. of ethanol and 10 ml. of water is refluxed for 5 hours. After thereaction mixture is cooled, hair-like crystals are formed in the flask.These crystals are collected by filtration and washed with diethyl etheryielding 2.4 g. (25%) of 1-(4,5-dihydro-2-thiazolyl)-1lj-benzimidazole-Z-thiol; m.p. 188189.

c. [l,1 -Biphenyl]-4-carbothioic acid, S-[1-(4,5- dihydro-2 -thiazolyl)-;l lj-benzimidazol-Z-yl]ester 0.31 g. (0.0125 moles) of sodium hydrideis added in small portions to a stirred solution of 2.0 g. (0.0085moles) of 1-( 4 ,5 -dihydro-2-thiazoly1 1 lj-benzimidazole-Z-thiol, frompart (b), in ml. of dry THF at room temperature. The resulting mixtureis warmed in a water bath at 40 for 0.5 hours and then cooled in an icebath to 0 while a solution of 2.3 g. (0.01 mole) of4-biphenylcarbonylchloride in 50 ml. of dry THF is added. This mixture is heated at refluxtemperature for 2.5 hours. The reaction mixture is cooled, filtered, andthe solids are washed with CHCI The combined washings and filtrate areconcentrated in vacuo. The residue is dissolved in 300 ml. of CHCL, andwashed with 200 ml. of a dilute solution of NaOH and twice with 200 ml.of water. The organic phase is dried (anhydrous MgSO and concentrated invacuo to yield 1.9 g. of crude material. This material is recrystallizedfrom acetone-hexane to give 1.2 g. (34%) of 1,1-biphenyll-4-carbothioicacid, S-[ 1-(4,5-dihydro- 2-thiazolyl l lj-benzimidazol-2-yl ]ester; m.p. l81.5183.

EXAMPLE 2 Octadecanethioic acid, S-[1-(4,5-dihydro-2-thiazolyl)-1fl-benzimidazol-2- yl]ester 0.31 g. (0.0125moles) of sodium hydride is added in small portions to a stirredsolution of 2.0 g. (0.0085 moles) of l-(4,5-dihydro-2-thiazolyl llj-benzimidazole-2-thiol, from example 1b, in 100 ml. of dry THF at roomtemperature. The resulting mixture is warmed in a water bath at 40 for0.66 hours and then cooled in an ice bath to 0 while a solution of 3.1g. (0.01 mole) of stearoyl chloride in 50 ml. of dry THF is added. Thismixture is heated at reflux temperature for 2.5 hours. The reactionmixture is cooled, filtered, and the solids are washed with CHCl Thecombined washings and filtrate are concentrated in vacuo. The residue isdissolved in 250 ml. of CHCl and washed with ml. of a dilute aqueousNaOH solution and three times with 150 ml. of water. The organic phaseis dried (anhydrous MgSO and concentrated in vacuo to yield a whitesolid residue. This residue is recrystallized from Tl-lF-methanol toyield 1.8 g. (43%) of octadecanethioic acid, S-[ 1-(4,5-dihydro-2-thiazolyl 1 I l-benzimidazol-2-yl]ester; m.p. 95-97.5.

EXAMPLE 3 Benzenepropanothioic acid, S-[ l-( 4 ,5-dihydro-2-thiazolyl 1lj-benzimidazol-Z- yl ]ester Following the procedure of example 1 butsubstituting 1.9 g. (0.0113 mole) of hydrocinnamoyl chloride for the4-biphenylcarbonyl chloride in part (c), one obtains a yellow solidresidue. This material is recrystallized twice from acetone-hexane toyield 1.5 g. (46%) of benzenepropanothioic acid,S-[1-(4,5-dihydro-2-thiazolyl)-1H-benzimidazol-Z-yl]-ester; m.p.112.5114.

EXAMPLE 4 1-(4,5-Dihydro-2-thiazolyl)-2-[(Phenylmethyl )thio]- lll-benzimidazole 11.75 g. (0.05 mole) of l-(4,5-dihydro-2-thiazolyl)-llj-benzimidazole-Z-thiol, from example lb, in 100 ml. of DMF is addedto a slurry of 1.32 g. (0.055 moles) sodium hydride in 50 ml. of dry DMFat room temperature. After stirring for two hours, a solution of 6.25 g.(0.055 moles) of benzyl chloride in 50 ml. of DMF is added. The mixtureis warmed to 70 for three hours. Upon cooling, the reaction mixture iscarefully diluted with two volumes of water. The oil that separates iswashed with water and then triturated with hexane. The solids that formare collected by filtration and recrystallized from ethanol to givel-(4,5-dihydro-2- thiazolyl )-2-[(phenylmethyl )-thio]- 1lj-benzimidazole.

EXAMPLES 5-38 Following the procedures of examples 1 to 4 but employingthe compounds of the formula R -halo listed below in column A, there areobtained the products of the following formula wherein R is the radicallisted in column B:

NO CH CH Br SCN (CH CI Col 8 n-c H SCN(CH Br Cl OCI DC I EXAMPLE 39 l-(4,5-Dihydro-2-thiazolyl lIj-benzimidazol-2- yl]thio]acetic acid, ethylester a. (Benzimidazol-Z-yl) .thioacetic acid, ethyl ester the mixtureis stirred overnight. Afterwards, the mixture is diluted with 3 volumesof water and extracted with ether. I The organic phase is dried(anhydrous MgSO and concentrated in vacuo to give an oil. The product ispurified by chromatography on neutral alumina (400 g., Act I) and elutedwith ethyl acetate-hexane. Crystallization from ethyl acetate-hexanegives 19 g. (41%) of (benzimidazol-2-yl)thioacetic acid, ethyl ester;m.p. 96.5.

b. l-( 4,5-Dihydro-2-thiazolyl)- l fl-benzimidazol-Z- yl]thio]-aceticacid, ethyl ester An oil dispersion (57% mineral oil) of 2.9 g. (0.07moles) of sodium hydride is added in small portions to a stirredsolution of 16.5 g. (0.07 moles) of (benzimidazol-2-yl)thioacetic acid,ethyl ester, from part (a), in 450 ml. of dry glyme. The resultingorange mixture is stirred at room temperature for 1 hour. Afterwards, asolution of 8.5 g. (0.07 moles) of 2-chloroethyl isothiocyanate in 50ml. of dry glyme is added dropwise. The resulting dark brown mixture isheated at reflux temperature for 3 hours and the solvent is removed invacuo. The residue is dissolved in 500 ml. of CHCl and washed withdilute l-lCl, dilute Nal-lCO and saturated brine. The organic phase isdried (anhydrous MgSO treated with charcoal, and concentrated in vacuo.The crude product is recrystallized from THF-water to yield 3.5 g. ofl-(4,5-dihydro-2- thiazolyl)-llil-benzimidazol-2-yl1thio]acetic acid,ethyl ester; m.p. 99l0l.5.

EXAMPLES 40-48 Following the procedure of example 1 but substituting forthe 2-bromoethyl isothiocyanate in part (a) the haloalkylisothiocyanatesshown in column A the product shown in column B is obtained.

Col A Col 8 haloZ-NCS F 7 i R] z :2

cH CH2 CH2 CH2 fH CH2 cum-1 cH CH CH2 CH CH2 Similarly, by employingthese haloalkylisothiocyanates in any of examples 2 to 39, othercompounds of formula I within the scope of this invention are prepared.

EXAMPLE 49 1 ,1 -Biphenyl]-4-carbothioic acid, S-[1-(4,5-dihydro-2-thiazolyl)-5(or 6 )-methyl- 1 lj-benzimidazol-Z-yl]ester a. l-(4,5-Dihydro-2-thiazolyl)-5(or6)-methyl-ll;lbenzimidazole-Z-thiol A solution of 6.85 g. (0.0416 mole)of 2-mercapto-5- methyl-benzimidazole [prepared by the general method ofVan Allan et. al., Org. Syn., Coll. Vol. 4, p. 569 (1963), m.p. 285292]in 270 ml. of dry glyme is stirred under nitrogen at room temperaurewith 4.05 g. (0.0955 mole) of 57% sodium hydride dispersion in mineraloil. After 1.5 hours, 10 g. (0.0832 mole) of 2-chloroethylisothiocyanate is added and the slurry is refluxed for 3 hours, cooled,and the solvent removed in vacuo. The residue is treated with methanolto decompose unreacted hydride and the methanol is removed in vacuo. Theresulting oil is triturated with hexane (hexane discarded) and the oilis partitioned between chloroform and water containing a slight excessof acetic acid. The chloroform solution is dried and the solvent removedin vacuo yielding 14.5 g. of crude product. A solution of 11.5 g. ofthis solid in 1:1 chloroform-hexane is chromatographed on a 225 g.alumina (neutral, activity 111) column. Elution with chloroform-hexanemixtures and then chloroform yields 4 g. of TLC pure material.Recrystallization from chloroform-hexane yields 2.4 g. ofl-(4,5-dihydro-2- thiazolyl)-5( or 6)-methy1-1Ll-benzimidazole-2-thiol;m.p. 197-l99.

b. [1,1'-Biphenyl]-4-carbothioic acid, S-[1-(4,5- dihydro-2-thiazolyl)-5( or 6 )-methyl- 1 lj-benzimidazol- 2-yl]ester Following theprocedure of example 1(c) but substituting thel-(4,5-dihydro-2-thiazo1yl)-5-(or 6)-methylllj-benzimidazole-Z-thiol forthe l-(4,5-dihydro-2- thiazolyl)-1lj-benzimidazole-Z-thiol, one obtainsthe titled product.

EXAMPLE [1,1 '-l3iphenyl]-4-carbothioic acid, S-'[5 or 6 )-chloro- 14,5-dihydro-2-thiazolyl 1 lj-benzimidazol-2-yl]ester a. 5(or6)-Chloro-1-(4,5-dihydro-2-thiazolyl)-l1:1- benzimidazole-Z-thiol Asolution of 7.7 g. (0.041 mole) of 5-chloro-ll lbenzimidazole-Z-thiol in270 ml. of dry glyme is stirred under nitrogen and 4.05 g. (0.0955 mole)of 57% sodium hydride dispersion in mineral oil is added. After stirringat room temperature for 1.5 hours, 12.5 g. (0.1035 mole) of2-chloroethyl isothiocyanate is added and the reaction mixture isrefluxed overnight. The solvent is removed in vacuo and the residue istriturated with methanol. After removal of the methanol in vacuo, hexaneis added and removed by decantation. The gummy residue is partitionedbetween chloroform and water. The chloroform extract is dried withsodium sulfate and evaporated in vacuo yielding 3.7 g. of crude product.This solid material is dissolved in chloroform and chromatographed on an80 g. alumina (neutral, activity [1) column. Elution with chloroformyields 3.0 g. of TLC pure product. Crystallization from methanol yields2.0 g. of 5(or 6)-chloro-1-(4,5-dihydro-2-thiazolyl)-llj-benzimidazole-Z-thiol; m.p. 248-250.

b. [1,1-Biphenyl]-4-carbothioic acid, S-[5(or 6)- chloro-1-(4,5-dihydro-Z-thiazolyl l lj-benzimidazol- 2-yl]ester Following the procedure ofexample 1(c) but substituting the 5(or6)-chloro-l-(4,5-dihydro-2-thiazolyl)- lH-benzimidazole-Z-thiol for thel-(4,5-dihydro-2- thiazolyl)-lH-benzimidazole-Z-thiol, one obtains thetitled product.

EXAMPLE 51 1,1 '-Biphenyl]-4-carbothioic acid, S-[l-(4,5-dihydro-2-thiazolyl)-5(or 6) -nitro-11:1-benzimidazol-2yl1estera. 1-( 4,5-Dihydro-2-thiazolyl )-5(or 6 )-nitrollj-benzimidazole-Z-thiol 9.75 g. (0.05 mole) of5-nitro-llj-benzimidazole-Z- thiol is added, portionwise, at roomtemperature to'a stirred slurry of 1.5 g. (0.06 mole) of sodium hydridein 400 ml. of dry glyme. After the evolution of hydrogen b.[1,1-Biphenyl]-4-carbothioic acid, S-[1-(4,5- dihydro-2-thiaz'olyl)-5(or 6)-nitro-1 lj-benzimidazol- 2yl]ester Following the-procedure ofexample 1(c) but substituting the l-(4,5-dihydro 2-thiazolyl)-5(or6)-nitro- 1lj-benzimidazole-2-thiol' for the l- (4,5-dihydro-2-thiazolyl)-llj-benzimidazole-2-thiol, one obtains the titled product.

EXAMPLES 52-70,

A Col Ex. 4 i 4 or 7 53 Br Br 54 CF CF 56 C H C H I C H 8 s oc u 0C2H559 Cl Cl O I C H CH C H C H 62 2 5 2 5 64 CC H I H C I H c 4 9 O O H n67 C-CH C-CH Also, the following disubstituted compounds are obtained.

Similarly, by following the procedures of Examples 49 to 51 but alsosubstituting for the 2-chloroethy1iso- EXAMPLE 71 A Butylcarbamothioicacid,

S-[ l-( 4,5-dihydro-2-thiazolyl 1 lj-benzimidazol-Z- yl ester To aslurry of'0.792 mg. (0.033 moles) of sodium hydride in 50 ml. of dry THFat room temperature there is added a solution of 7.05 g. (0.03 moles) of1-( 4,5-dihyd ro-2-thiazolyl l lj-benzimidazole-Z-thiol, from examplelb, in ml. of THF. After stirring for 1 hour, a solution of 2.97 g.(0.03 moles) of butyl isocyanate in 50 ml. of THF is added. Theresulting mixture is heated at reflux temperature for 4 hours. The THFis removed in vacuo and the residue is partitioned between CHCl andwater. The organic fraction is washed twice with water, dried over CaCland concentrated in vacuo. The purified butylcarbamothioic acid. S-[ l-(4,5-dihydro-2-thiazolyl)-1lj-benzimidazol-Z-yl]ester is obtained bycrystallization from acetone-hexane.

EXAMPLES 72-75 Following the procedure of example 71 but substitutingfor the butyl isocyanate the compounds listed below in column A, thereis obtained respectively the compound of the following formula wherein Ris the radical listed in column B:

Ex. CoLA Similarly, by following the procedure of example 7l EXAMPLE 76[1,1 '-Biphenyl]-4-carbothioic acid, S-[5(or6)-amino-l-(4,5-dihydro-2-thiazolyl-1lj-benzimidazol- 2-yl]ester,hydrochloride 1,1 '-Biphenyl]-4-carbothioic acid, S-[1-(4,5-dihydro-2-thiazolyl )-5 or 6 )-nitrol lj-benzimidazol-2- yl]esterfrom Example 51 in 200 ml. of ethanol is reduced with hydrogen overRaney Nickel catalyst at a pressure of 3 to 4 atmospheres. The catalystis removed by filtration and the filtrate is reduced in vacuo to avolume of about 50 ml. and then saturated with dry HC]. Upon standing,the hydrochloride precipitates and is purified by crystallization fromethanol yielding the [1,1-biphenyl]-4-carbothioic acid, S-[5(or 6)-amino- 1 -(4,5-dihydro-2-thiazolyl)- l lj-benzimidazol-2- yl]ester,hydrochloride.

What is claimed is:

1. A compound of the formula:

S-R w n N7l/s V wherein Z is ethylene or propylene; R is hydrogen,methyl, ethyl, phenyl, nitrophenyl, benzyl, phenethyl, tolyl, or xylyl;R is alkyl of 1, to 5 carbons, benzyl, nitrobenzyl, phenethyl,nitrophe'nethyl, alkoxycarbonylalkylene wherein alkoxy is of 1 to 5carbons and;

alkylene is of 1 to 3 carbons, dialkylaminoalkylene wherein each alkylis of 1 to 3 carbons and alkylene is of 2 or 3 carbons, alkanoyl of from2 to 18 carbons, benzoyl, substituted benzoyl wherein said substituentis halogen, alkyl of l to 3 carbons, or phenyl, phenylmethylcarbonyl,phenethylcarbonyl,

wherein R and Z are as defined above,

wherein alkyl is of l to 5 carbons, or

X is oxygen or sulfur; R is alkyl of l to 3 carbons, phenyl, benzyl, orphenethyl; R is hydrogen, halogen, nitro, amino, cyano, trifluoromethyl,alkyl of 1 to 3 carbons alkoxy of l to 3 carbons, dialkvlamino whereineach alkyl is of 1 to 3 carbons, alkanoyl of 2 to 6 carbons, or benzoyl;and n is l or 2; and when R is dialkylaminoalkylene or R is amino ordialkylamino the pharmaceutically acceptable acid-addition salts.

2. The compound of claim 1 wherein R is hydrogen; n is one; R is benzoylor substituted benzoyl wherein said substituent is halogen, alkyl of lto 3 carbons, or phenyl; and R is hydrogen, halogen, nitro, or alkyl of1 to 3 carbons.

3. The compound of claim 2 wherein Z is ethylene.

4. The compound of claim 3 wherein R is hydrogen, methyl or Cl.

5. The compound of claim 4 wherein R is hydrogen and R is(p-phenyl)benzoyl.

6. The compound of claim 1 wherein Z is ethylene; R and R are hydrogen;and R is 7. The compound of claim 1 wherein Z is ethylene; R and R arehydrogen; and R is 8. The compound of claim 1 wherein Z is ethylene; Rand R are hydrogen; and R is UNITED STATES PATENT AND TRADEMARK OFFICEETFIQATE 0F CORRECTION PATENT NO. I 3,927,014 DATED December 16, 1975INV ENTOR(S) G. Rovnyak et a1 It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Col,

4 line 22, "Similarly, compounds" should start a new paragraph.

Col, 4, line 42, "2-pheny" should read -2phenyl.

Col, 5, line 62, "thiazoline," should read -thiazoline.-.

Col, 6, line 9, "0.31 g.," should read-0.31 g..

Col. 9, line 60, "a. (Benzimidazol-Z-yl) should start a new paragraph.

Col ll, line 43, "temperaure" should read temperature-.

Col. 12, line 42, "2yl" should read -2-yl--.

Col. 12, line 63, "2yl" should read --2-yl.

Signed and Sealed this fourth Day of May 1976 A ttest:

RUTH C. MASON Arresting Officer C. MARSHALL DANN (ummissiuner uj'lanmtsand Trademarks

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 wherein R1 ishydrogen; n is one; R2 is benzoyl or substituted benzoyl wherein saidsubstituent is halogen, alkyl of 1 to 3 carbons, or phenyl; and R3 ishydrogen, halogen, nitro, or alkyl of 1 to 3 carbons.
 3. The compound ofclaim 2 wherein Z is ethylene.
 4. The compound of claim 3 wherein R3 ishydrogen, methyl or Cl.
 5. The compound of claim 4 wherein R3 ishydrogen and R2 is (p-phenyl)benzoyl.
 6. The compound of claim 1 whereinZ is ethylene; R1 and R3 are hydrogen; and R2 is
 7. The compound ofclaim 1 wherein Z is ethylene; R1 and R3 are hydrogen; and R2 is
 8. Thecompound of claim 1 wherein Z is ethylene; R1 and R3 are hydrogen; andR2 is